Leukemia · 2026
Множественная миелома - риск распространения и развития.
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Maeng CV, Thorsteinsdóttir S, Óskarsson JÞ, Rögnvaldsson S, Long TE, Brieghel C, Andersen MN, Ólafsson A, Þórðardóttir ÁR, Viðarsson B, Önundarson PT, Agnarsson BA, Sigurðardóttir M, Þorsteinsdóttir I, Ólafsson Í, Eyþórsson E, Jónsson Á, Harding S, Landgren O, Love TJ, Grønbæk K, Niemann CU, Kristinsson SY
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Оригинал публикации
Redefining light-chain smoldering multiple myeloma: prevalence and progression risk.
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Introduction
Smoldering multiple myeloma (SMM) is a precursor to multiple myeloma (MM) and present in 0.5% of the population over 40 years old [ 1 , 2 ]. In 10–20% of MM patients, the clonal BMPC do not produce intact M proteins but only free light chains (FLC) [ 3 , 4 ]. This subgroup termed light-chain MM and well-characterized, but light-chain SMM is not clearly defined.
Historically, monoclonal FLC were detected by urine protein electrophoresis (UPEP), but methods of detecting FLC in serum have become widely available and are used to infer the presence of monoclonal FLC. The higher sensitivity of serum FLC analysis and the convenience of a single blood sample over a 24-h urine collection have made this the preferred method for evaluating monoclonal gammopathies in clinical practice [ 5 – 7 ].
The only prior study on light-chain SMM, a single-center retrospective analysis, defined the diagnosis based on urinary monoclonal FLC (≥0.5 g/24 h) and/or >10% BMPC, in the absence of intact serum M protein and end-organ damage [ 8 ]. However, this study lacked FLC measurements in many cases, and bone marrow evaluation was missing in up to 40%. In addition, some individuals (27 of 73 tested) would now meet criteria for MM due to an FLC ratio >100. Thus, a refined diagnostic criteria and characterization of light-chain SMM is needed.
The aim of this study was to define and characterize light-chain SMM using FLC analysis and bone marrow sampling within the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study. In addition, to externally validate the proposed definition in a population-based clinical cohort in Denmark (the Danish Lymphoid-lineage Cancer Research; DALY-CARE) and to estimate the progression risk.
Methods
iStopMM
The iStopMM study is a nationwide screening study [ 9 ], summarized in Supplementary Methods. For this study, we defined light-chain SMM by an abnormal FLC ratio and elevation of the involved FLC according to the iStopMM revised FLC reference ranges [ 10 , 11 ], a BMPC 10–59% and absence of M protein and myeloma defining events [ 5 ]. The Mayo Clinic 2/20/20 risk stratification model was used to stratify patients into risk groups. Mass spectrometry (MS) on blood samples and next-generation flow (NGF) on bone marrow samples was performed (elaborated in Supplementary Methods).
Estimates of the proportion of light-chain SMM among individuals with abnormal FLC levels, as well as prevalence calculations for light-chain SMM, were based on individuals randomized to bone marrow sampling and CT scan regardless of laboratory results (Study Arm 3, Supplementary Methods). The point prevalence was determined with a fitted binomial function corrected for age and sex. The standard errors of the fit were used to calculate 95% confidence intervals (CIs) of the prevalence.
DALY-CARE
The DALY-CARE data resource [ 12 ] is a nationwide collection of Danish registries and databases. The SMM cohort was defined as individuals with an ICD-10 coded MM diagnosis who had not died or received anti-myeloma treatment within 90 days of diagnosis. Pathology reports were evaluated to confirm BMPC infiltration of 10–59% in bone marrow biopsy within 90 days of diagnosis. Light-chain SMM was defined as SMM individuals without a detected intact heavy-chain M protein and abnormal values and ratio of FLC at diagnosis. Further details on data and cohort construction in Supplementary Methods and Supplementary Fig. 1 .
Progression was defined as start of anti-myeloma treatment or diagnosis of amyloid light-chain (AL) amyloidosis. Individuals were followed from diagnosis to progression, death, or end of follow-up. The median follow-up was calculated using reversed Kaplan–Meier. Overall cumulative incidences were calculated using Aalen-Johansen estimation, accounting for death as a competing risk, and Kaplan–Meier estimation, when not accounting for death as competing risk. Average annual progression rate was calculated as the number of observed progressions per person-year.
Individuals were stratified into 2/20/20 risk groups and cumulative incidence of progression were estimated for each strata. Gray´s test was used to test differences of cumulative incidence curves.
Results
iStopMM
A total of 75,422 individuals underwent screening between 2016 and 2020. Of these, 3788 individuals had an abnormal screening test and were randomized to one of the three study arms. A total of 193 participants had SMM based on initial evaluation (Supplementary Fig. 1 ), of which 23 fulfilled our suggested criteria for light-chain SMM. The cohort characteristics and laboratory results are summarized in Table 1 . In addition to the MS results shown in Table 1 , IgM peaks below the detection limit of SPEP (0.0015–0.005 g/dl in size) without an associated light chain were identified in 8 individuals (40%).
Table 1 Baseline characteristics of individuals with light chain smoldering multiple myeloma. Variable Light-chain SMM in iStopMM ( n = 23) Light-chain SMM in DALY-CARE ( n = 88) Age, years 69 (56–77) 73 (66–80) Sex Male 16 (70) 53 (60) Female 7 (30) 35 (40) Laboratory values Hemoglobin, g/dL 14.3 (13.1–14.5) 13.2 (11.8–14.0) Creatinine, µmol/L 85 (73–92.5) 80 (66–107) Calcium, mmol/L 2.4 (2.34–2.39) 2.4 (2.3–2.5) Free kappa, mg/L 52.4 (10.2–232.2) 200 (20–441) Free lambda, mg/L 14 (10.2–154.0) 16 (11–251) Involved/uninvolved FLC ratio >20 11 (47) 56 (64) Immunofixation Negative 13 (57) 61 (76) Kappa 4 (17) 4 (5) Lambda 6 (26) 15 (19) Missing 8 Isotype (according to FLC analysis) Kappa 15 (65) 60 (68) Lambda 8 (35) 28 (32) 24-h UPEP and immunofixation results Detectable 13 (72) 31 (63) Not detectable 5 (28) 18 (37) Missing 5 39 Isotype of urinary light-chain, if detectable Kappa 10 (55) 17 (54) Lambda 3 (17) 13 (46) Missing 0 1 Quantification of urinary light-chain, if detectable Median g/24 h 0.18 g (<0.10–0.61) 0.02 g (0.02–0.26) >0.2 g/24 h 4 (22) 6 (26) >0.5 g/24 h 2 (11) 3 (13) Missing 5 8 Mass spectrometry results 20 (87) Kappa peak 11 (55) Lambda peak 8 (40) Not available IgG (0.029 g/dL) and a kappa peak 1 (5) IgA (<0.005 g/dL) 1 (5) Bone marrow plasma cells 10–19% 20 (87) 56 (64) 20–59% 3 (13) 32 (36) Next generation flow results 19 (83) Detectable plasma cell clone in BM 19 (100) Not available >95% aberrant plasma cells 6 (32) Number of suppressed immunoglobulins 1 3 (13) 23 (27) 2-3 6 (26) 37 (44) Immunoglobulins >25% below normal range 3 (13) 44 (52) Data not available 1 3 Risk group by 2/20/20 risk mode l Low risk, no. (%) 11 (48) 23 (26) Intermediate risk, no. (%) 10 (43) 44 (48) High risk, no. (%) 2 (9) 21 (23) Data is presented as median (interquartal range) for continuous variables and number (%) for categorical variables. BM bone marrow, FLC free light chain, IQR interquartal range, SMM smoldering multiple myeloma, MM multiple myeloma, PB peripheral blood, UPEP urine protein electrophoresis.
Baseline characteristics of individuals with light chain smoldering multiple myeloma.
Data is presented as median (interquartal range) for continuous variables and number (%) for categorical variables.
BM bone marrow, FLC free light chain, IQR interquartal range, SMM smoldering multiple myeloma, MM multiple myeloma, PB peripheral blood, UPEP urine protein electrophoresis.
AL amyloidosis was screened for with N-terminal pro B-type natriuretic peptide and troponin T measurements in 19 (83%) patients and Congo red staining of bone marrow biopsies in 14 (61%) individuals. No cases of AL amyloidosis were diagnosed.
A total of 1303 individuals were randomized to bone marrow examination and CT scan regardless of SPEP and FLC results. Of these, 105 (8%) had an abnormal FLC analysis and no detectable intact monoclonal immunoglobulins on SPEP. Of those, 86 underwent bone marrow sampling, of whom 16 (19%) had >10% BMPC fulfilling our suggested criteria for light-chain SMM. A total of 112 (11% of those with bone marrow sampling performed) individuals had >10% BMPC and no myeloma defining events. The proportion of light-chain SMM of all SMM in this sub-cohort was therefore 14% (16/112). The prevalence of light-chain SMM in individuals over 40 years old was estimated to be 0.08% (95% CI: 0.07–0.10%), 0.07% (95% CI: 0.05–0.10%) in women, and 0.09% (95% CI: 0.07–0.12%) in men.
The DALY-CARE cohort
A total of 88 patients in the Danish cohort fulfilled the set criteria for light-chain SMM. The cohort characteristics and laboratory results at diagnosis are summarized in Table 1 . The median follow-up was 5.2 years (IQR 2.2–8.3 years). During follow-up, 17 (19%) patients progressed (16 to MM and one to AL amyloidosis), and 30 (34%) died without progression. The estimated cumulative incidence of progression was 8.1 (95% CI: 1.6–14.2%) two years from light-chain SMM diagnosis and 29.5% (95% CI: 14.7–41.8%) at five years. When death was considered a competing risk, the cumulative incidence was 7.4% (95% CI: 1.7–13.2%) two years from light-chain SMM diagnosis and 23.0% (95% CI: 12.5–33.5%) (Fig. 1A ). The annualized average progression rate was 6.0% (95% CI 3.5–9.6) (17 progressions during 282 person-years).
Cumulative incidence of progression in light-chain smoldering multiple myeloma with death as competing risk.
A Cumulative progression to multiple myeloma or amyloid light-chain amyloidosis over time in 88 individuals in the DALY-CARE cohort. B Cumulative progression to multiple myeloma or amyloid light-chain amyloidosis over time by risk group according to the 2/20/20 risk stratification criteria.
Of the 88 individuals with available data for risk stratification according to the 2/20/20 model, 23 (26%) classified as low-risk and 65 (74%) as intermediate- or high-risk SMM. For the low-risk group, no progressions occurred during follow-up. For the intermediate/high-risk individuals, the cumulative incidence was 9.8% (95% CI 2.4–17.3) at two years and 30.3% (95% CI 17.1–43.5) at five years considering death as competing risk (Fig. 1B ). The annual rate of progression was 9.2% (95% CI 5.4–14.7) for intermediate/high risk individuals. Of the 16 individuals who progressed to MM, anemia was present in 10 (63%) and renal insufficiency in 8 (50%) at progression. FLC ratio >100 was observed in 10 (63%), of whom 9 also met at least one additional MM diagnostic criterion. For cases with available clinical treatment indications from EHR ( n = 8), anemia, renal impairment, or bone disease led to treatment initiation in five cases, and rapidly rising FLC levels or FLC ratio >100 in three.
Discussion
We propose to revise the definition of light-chain SMM to abnormal serum FLC values, absence of detectable intact immunoglobulin on SPEP and immunofixation, and BMPC > 10% without myeloma-defining events. From nationwide screening and systematic bone marrow sampling, we determined that 19% of individuals with abnormal FLC levels had light-chain SMM, corresponding to a population prevalence of 0.08% among individuals over 40 years.
This definition reflects current practice, where serum FLC testing has increasingly replaced UPEP for detecting and monitoring monoclonal light-chain disorders. UPEP was negative in 28% of light-chain SMM cases with available data in iStopMM and 37% in DALY-CARE, suggesting that FLC analysis may be more sensitive for detection. Although Kyle et al. [ 8 ] found that 12% of individuals with a detectable Bence Jones proteinuria had a normal FLC ratio (0.26–1.65), indicating that UPEP can be more sensitive in some cases, this requires reassessment using revised FLC reference intervals [ 10 , 11 ]. While 24-h urine testing may contribute to risk stratification, it is burdensome and may not be necessary at initial evaluation if serum FLC testing is available.
In DALY-CARE, light-chain SMM was associated with an annual progression risk of ~6%, which is similar to previously reported progression risk [ 8 ] and higher than for light-chain MGUS [ 13 ]. Among individuals with at least one high-risk feature by the 2/20/20 model [ 14 ], annual progression risk was ~9%. These findings support close clinical surveillance and further studies of risk stratification in this subgroup.
Strengths of our study include the population-based screened design of the iStopMM study, systematic bone marrow biopsies per protocol, and complete FLC analysis for all screened participants. Furthermore, state-of-the-art evaluations with MALDI-TOF-MS and NGF support our observations. Our findings were confirmed in a large population-based Danish cohort and describe the risk of progression.
In conclusion, light-chain SMM defined by abnormal FLC analysis, no detectable immunoglobulin heavy chain by SPEP or immunofixation, and BMPC 10–59% without myeloma-defining events identifies individuals with an annual progression risk of ~6%. This definition may improve early identification and monitoring strategies.
Supplementary information
Supplementary
Acknowledgements
We gratefully acknowledge the late Brian G. M. Durie, whose important contributions to the iStopMM study and to this work were invaluable. We sincerely thank participants and staff for their dedication and hard work in both the iStopMM study and the Danish registries, particularly the Danish Multiple Myeloma Registry, which were of great importance to this study.
Author contributions
SYK, ST and CVM were responsible for concept and design of the study. Data analyses were preformed by ST (iStopMM data) and CVM (DALY-CARE data). CVM, ST, JÞÓ, SR, CB, MNA, BV,PTÖ, BAA, MS, IÞ, ÍÓ, EE, ÁJ, TJL, KG, and CUN contributed to acquisition of data and interpretation of results. ST, CVM and SYK drafted the manuscript. ST, CVM, JÞÓ, SR, CB, MNA, SH, OL, KG, CUN, and SYK provided critical review of the manuscript for important intellectual content.
Funding
CVM was funded by the Danish Cancer Society (Grant no. OV25-02363 and R352-A20533) and the Alfred Benzon Foundation. ST was funded by Rigshospitalet Research Foundation and the European Hematology Association. The iStopMM study is funded by the Black Swan Research Initiative of the International Myeloma Foundation, the European Research Council under the European Union´s Horizon program (Grants 716677 and 101045549), the Icelandic Centre for Research (Grants 228524-051 and 217987-051), Blood Cancer United (2340-23), the Rising Tide Foundation (CCR-24-160), the Icelandic Cancer Society, the Landspítali Research Fund, the Nordic Cancer Union, the World Cancer Research Fund (IIG_FULL_2024_040), the International Myeloma Society – Paula and Rodger Riney Foundation Translational Research Award, and the University of Iceland. Screening tests were provided by The Binding Site Ltd., part of Thermo Fisher Scientific. Open access funding provided by National Hospital.
Data availability
De-identified data from iStopMM are available from the corresponding author upon reasonable request, subject to approval by the iStopMM investigators and the Icelandic National Bioethics Committee. Data from the DALY-CARE data resource can be accessed on a collaborative basis within the restrictions from the Danish National Ethics Committee. R codes are available upon request from corresponding author.
Competing interests
ST reports honoraria for scientific presentations from AbbVie, GlaxoSmithKline, Takeda and Thermo Fisher Scientific; advisory board participation for Sanofi; a travel grant from Amgen; and conference participation supported by GlaxoSmithKline outside the submitted work. CVM has participated in a conference supported by Daiichi Sankyo. SR reports honoraria for scientific talks from Johnson & Johnson and Siemens Healthineers. CB has received travel grants from AbbVie and AstraZeneca. CUN has received research funding from AbbVie, Johnson & Johnson, AstraZeneca, the Novo Nordisk Foundation, Genmab, and Octapharma, and has served as a consultant for AbbVie, BeiGene, Janssen, Roche, AstraZeneca, CSL Behring, Genmab, Takeda, Octapharma, MSD, Synamics, and Lilly. KG has received research funding from Janssen. SH is employed at Thermo Fisher Scientific. OL reports grants from Amgen, Johnson & Johnson, and Pfizer; service on independent data monitoring committees for Johnson & Johnson, Takeda, and Merck; and personal fees from Sanofi, Johnson & Johnson, and Pfizer outside the submitted work. SYK reports research funding from Amgen and Celgene and service on an independent data monitoring committee for Johnson & Johnson outside the submitted work. The remaining authors had no conflict of interest.
Ethics approval and consent to participate
The iStopMM study was approved by the Icelandic National Bioethics Committee (Number 16–022, date: 2016-04-26) and the Icelandic Data Protection Agency and all participants provided informed consent. The study in DALY-CARE was approved by the Danish Health Data Authority (P-2020-561) and National Ethics Committee (1804410). Under Danish legislation, register studies are exempt from informed consent.
Footnotes
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
These authors contributed equally: Cecilie Velsoe Maeng, Sigrún Thorsteinsdóttir.
Supplementary information
The online version contains supplementary material available at 10.1038/s41375-026-03028-8.
References
Associated Data
Supplementary Materials
Supplementary
Data Availability Statement
De-identified data from iStopMM are available from the corresponding author upon reasonable request, subject to approval by the iStopMM investigators and the Icelandic National Bioethics Committee. Data from the DALY-CARE data resource can be accessed on a collaborative basis within the restrictions from the Danish National Ethics Committee. R codes are available upon request from corresponding author.
Smoldering multiple myeloma (SMM) is a precursor to multiple myeloma (MM) and present in 0.5% of the population over 40 years old [ 1 , 2 ]. In 10–20% of MM patients, the clonal BMPC do not produce intact M proteins but only free light chains (FLC) [ 3 , 4 ]. This subgroup termed light-chain MM and well-characterized, but light-chain SMM is not clearly defined.
Historically, monoclonal FLC were detected by urine protein electrophoresis (UPEP), but methods of detecting FLC in serum have become widely available and are used to infer the presence of monoclonal FLC. The higher sensitivity of serum FLC analysis and the convenience of a single blood sample over a 24-h urine collection have made this the preferred method for evaluating monoclonal gammopathies in clinical practice [ 5 – 7 ].
The only prior study on light-chain SMM, a single-center retrospective analysis, defined the diagnosis based on urinary monoclonal FLC (≥0.5 g/24 h) and/or >10% BMPC, in the absence of intact serum M protein and end-organ damage [ 8 ]. However, this study lacked FLC measurements in many cases, and bone marrow evaluation was missing in up to 40%. In addition, some individuals (27 of 73 tested) would now meet criteria for MM due to an FLC ratio >100. Thus, a refined diagnostic criteria and characterization of light-chain SMM is needed.
The aim of this study was to define and characterize light-chain SMM using FLC analysis and bone marrow sampling within the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study. In addition, to externally validate the proposed definition in a population-based clinical cohort in Denmark (the Danish Lymphoid-lineage Cancer Research; DALY-CARE) and to estimate the progression risk.
Methods
iStopMM
The iStopMM study is a nationwide screening study [ 9 ], summarized in Supplementary Methods. For this study, we defined light-chain SMM by an abnormal FLC ratio and elevation of the involved FLC according to the iStopMM revised FLC reference ranges [ 10 , 11 ], a BMPC 10–59% and absence of M protein and myeloma defining events [ 5 ]. The Mayo Clinic 2/20/20 risk stratification model was used to stratify patients into risk groups. Mass spectrometry (MS) on blood samples and next-generation flow (NGF) on bone marrow samples was performed (elaborated in Supplementary Methods).
Estimates of the proportion of light-chain SMM among individuals with abnormal FLC levels, as well as prevalence calculations for light-chain SMM, were based on individuals randomized to bone marrow sampling and CT scan regardless of laboratory results (Study Arm 3, Supplementary Methods). The point prevalence was determined with a fitted binomial function corrected for age and sex. The standard errors of the fit were used to calculate 95% confidence intervals (CIs) of the prevalence.
DALY-CARE
The DALY-CARE data resource [ 12 ] is a nationwide collection of Danish registries and databases. The SMM cohort was defined as individuals with an ICD-10 coded MM diagnosis who had not died or received anti-myeloma treatment within 90 days of diagnosis. Pathology reports were evaluated to confirm BMPC infiltration of 10–59% in bone marrow biopsy within 90 days of diagnosis. Light-chain SMM was defined as SMM individuals without a detected intact heavy-chain M protein and abnormal values and ratio of FLC at diagnosis. Further details on data and cohort construction in Supplementary Methods and Supplementary Fig. 1 .
Progression was defined as start of anti-myeloma treatment or diagnosis of amyloid light-chain (AL) amyloidosis. Individuals were followed from diagnosis to progression, death, or end of follow-up. The median follow-up was calculated using reversed Kaplan–Meier. Overall cumulative incidences were calculated using Aalen-Johansen estimation, accounting for death as a competing risk, and Kaplan–Meier estimation, when not accounting for death as competing risk. Average annual progression rate was calculated as the number of observed progressions per person-year.
Individuals were stratified into 2/20/20 risk groups and cumulative incidence of progression were estimated for each strata. Gray´s test was used to test differences of cumulative incidence curves.
Results
iStopMM
A total of 75,422 individuals underwent screening between 2016 and 2020. Of these, 3788 individuals had an abnormal screening test and were randomized to one of the three study arms. A total of 193 participants had SMM based on initial evaluation (Supplementary Fig. 1 ), of which 23 fulfilled our suggested criteria for light-chain SMM. The cohort characteristics and laboratory results are summarized in Table 1 . In addition to the MS results shown in Table 1 , IgM peaks below the detection limit of SPEP (0.0015–0.005 g/dl in size) without an associated light chain were identified in 8 individuals (40%).
Table 1 Baseline characteristics of individuals with light chain smoldering multiple myeloma. Variable Light-chain SMM in iStopMM ( n = 23) Light-chain SMM in DALY-CARE ( n = 88) Age, years 69 (56–77) 73 (66–80) Sex Male 16 (70) 53 (60) Female 7 (30) 35 (40) Laboratory values Hemoglobin, g/dL 14.3 (13.1–14.5) 13.2 (11.8–14.0) Creatinine, µmol/L 85 (73–92.5) 80 (66–107) Calcium, mmol/L 2.4 (2.34–2.39) 2.4 (2.3–2.5) Free kappa, mg/L 52.4 (10.2–232.2) 200 (20–441) Free lambda, mg/L 14 (10.2–154.0) 16 (11–251) Involved/uninvolved FLC ratio >20 11 (47) 56 (64) Immunofixation Negative 13 (57) 61 (76) Kappa 4 (17) 4 (5) Lambda 6 (26) 15 (19) Missing 8 Isotype (according to FLC analysis) Kappa 15 (65) 60 (68) Lambda 8 (35) 28 (32) 24-h UPEP and immunofixation results Detectable 13 (72) 31 (63) Not detectable 5 (28) 18 (37) Missing 5 39 Isotype of urinary light-chain, if detectable Kappa 10 (55) 17 (54) Lambda 3 (17) 13 (46) Missing 0 1 Quantification of urinary light-chain, if detectable Median g/24 h 0.18 g (<0.10–0.61) 0.02 g (0.02–0.26) >0.2 g/24 h 4 (22) 6 (26) >0.5 g/24 h 2 (11) 3 (13) Missing 5 8 Mass spectrometry results 20 (87) Kappa peak 11 (55) Lambda peak 8 (40) Not available IgG (0.029 g/dL) and a kappa peak 1 (5) IgA (<0.005 g/dL) 1 (5) Bone marrow plasma cells 10–19% 20 (87) 56 (64) 20–59% 3 (13) 32 (36) Next generation flow results 19 (83) Detectable plasma cell clone in BM 19 (100) Not available >95% aberrant plasma cells 6 (32) Number of suppressed immunoglobulins 1 3 (13) 23 (27) 2-3 6 (26) 37 (44) Immunoglobulins >25% below normal range 3 (13) 44 (52) Data not available 1 3 Risk group by 2/20/20 risk mode l Low risk, no. (%) 11 (48) 23 (26) Intermediate risk, no. (%) 10 (43) 44 (48) High risk, no. (%) 2 (9) 21 (23) Data is presented as median (interquartal range) for continuous variables and number (%) for categorical variables. BM bone marrow, FLC free light chain, IQR interquartal range, SMM smoldering multiple myeloma, MM multiple myeloma, PB peripheral blood, UPEP urine protein electrophoresis.
Baseline characteristics of individuals with light chain smoldering multiple myeloma.
Data is presented as median (interquartal range) for continuous variables and number (%) for categorical variables.
BM bone marrow, FLC free light chain, IQR interquartal range, SMM smoldering multiple myeloma, MM multiple myeloma, PB peripheral blood, UPEP urine protein electrophoresis.
AL amyloidosis was screened for with N-terminal pro B-type natriuretic peptide and troponin T measurements in 19 (83%) patients and Congo red staining of bone marrow biopsies in 14 (61%) individuals. No cases of AL amyloidosis were diagnosed.
A total of 1303 individuals were randomized to bone marrow examination and CT scan regardless of SPEP and FLC results. Of these, 105 (8%) had an abnormal FLC analysis and no detectable intact monoclonal immunoglobulins on SPEP. Of those, 86 underwent bone marrow sampling, of whom 16 (19%) had >10% BMPC fulfilling our suggested criteria for light-chain SMM. A total of 112 (11% of those with bone marrow sampling performed) individuals had >10% BMPC and no myeloma defining events. The proportion of light-chain SMM of all SMM in this sub-cohort was therefore 14% (16/112). The prevalence of light-chain SMM in individuals over 40 years old was estimated to be 0.08% (95% CI: 0.07–0.10%), 0.07% (95% CI: 0.05–0.10%) in women, and 0.09% (95% CI: 0.07–0.12%) in men.
The DALY-CARE cohort
A total of 88 patients in the Danish cohort fulfilled the set criteria for light-chain SMM. The cohort characteristics and laboratory results at diagnosis are summarized in Table 1 . The median follow-up was 5.2 years (IQR 2.2–8.3 years). During follow-up, 17 (19%) patients progressed (16 to MM and one to AL amyloidosis), and 30 (34%) died without progression. The estimated cumulative incidence of progression was 8.1 (95% CI: 1.6–14.2%) two years from light-chain SMM diagnosis and 29.5% (95% CI: 14.7–41.8%) at five years. When death was considered a competing risk, the cumulative incidence was 7.4% (95% CI: 1.7–13.2%) two years from light-chain SMM diagnosis and 23.0% (95% CI: 12.5–33.5%) (Fig. 1A ). The annualized average progression rate was 6.0% (95% CI 3.5–9.6) (17 progressions during 282 person-years).
Cumulative incidence of progression in light-chain smoldering multiple myeloma with death as competing risk.
A Cumulative progression to multiple myeloma or amyloid light-chain amyloidosis over time in 88 individuals in the DALY-CARE cohort. B Cumulative progression to multiple myeloma or amyloid light-chain amyloidosis over time by risk group according to the 2/20/20 risk stratification criteria.
Of the 88 individuals with available data for risk stratification according to the 2/20/20 model, 23 (26%) classified as low-risk and 65 (74%) as intermediate- or high-risk SMM. For the low-risk group, no progressions occurred during follow-up. For the intermediate/high-risk individuals, the cumulative incidence was 9.8% (95% CI 2.4–17.3) at two years and 30.3% (95% CI 17.1–43.5) at five years considering death as competing risk (Fig. 1B ). The annual rate of progression was 9.2% (95% CI 5.4–14.7) for intermediate/high risk individuals. Of the 16 individuals who progressed to MM, anemia was present in 10 (63%) and renal insufficiency in 8 (50%) at progression. FLC ratio >100 was observed in 10 (63%), of whom 9 also met at least one additional MM diagnostic criterion. For cases with available clinical treatment indications from EHR ( n = 8), anemia, renal impairment, or bone disease led to treatment initiation in five cases, and rapidly rising FLC levels or FLC ratio >100 in three.
Discussion
We propose to revise the definition of light-chain SMM to abnormal serum FLC values, absence of detectable intact immunoglobulin on SPEP and immunofixation, and BMPC > 10% without myeloma-defining events. From nationwide screening and systematic bone marrow sampling, we determined that 19% of individuals with abnormal FLC levels had light-chain SMM, corresponding to a population prevalence of 0.08% among individuals over 40 years.
This definition reflects current practice, where serum FLC testing has increasingly replaced UPEP for detecting and monitoring monoclonal light-chain disorders. UPEP was negative in 28% of light-chain SMM cases with available data in iStopMM and 37% in DALY-CARE, suggesting that FLC analysis may be more sensitive for detection. Although Kyle et al. [ 8 ] found that 12% of individuals with a detectable Bence Jones proteinuria had a normal FLC ratio (0.26–1.65), indicating that UPEP can be more sensitive in some cases, this requires reassessment using revised FLC reference intervals [ 10 , 11 ]. While 24-h urine testing may contribute to risk stratification, it is burdensome and may not be necessary at initial evaluation if serum FLC testing is available.
In DALY-CARE, light-chain SMM was associated with an annual progression risk of ~6%, which is similar to previously reported progression risk [ 8 ] and higher than for light-chain MGUS [ 13 ]. Among individuals with at least one high-risk feature by the 2/20/20 model [ 14 ], annual progression risk was ~9%. These findings support close clinical surveillance and further studies of risk stratification in this subgroup.
Strengths of our study include the population-based screened design of the iStopMM study, systematic bone marrow biopsies per protocol, and complete FLC analysis for all screened participants. Furthermore, state-of-the-art evaluations with MALDI-TOF-MS and NGF support our observations. Our findings were confirmed in a large population-based Danish cohort and describe the risk of progression.
In conclusion, light-chain SMM defined by abnormal FLC analysis, no detectable immunoglobulin heavy chain by SPEP or immunofixation, and BMPC 10–59% without myeloma-defining events identifies individuals with an annual progression risk of ~6%. This definition may improve early identification and monitoring strategies.
Supplementary information
Supplementary
Acknowledgements
We gratefully acknowledge the late Brian G. M. Durie, whose important contributions to the iStopMM study and to this work were invaluable. We sincerely thank participants and staff for their dedication and hard work in both the iStopMM study and the Danish registries, particularly the Danish Multiple Myeloma Registry, which were of great importance to this study.
Author contributions
SYK, ST and CVM were responsible for concept and design of the study. Data analyses were preformed by ST (iStopMM data) and CVM (DALY-CARE data). CVM, ST, JÞÓ, SR, CB, MNA, BV,PTÖ, BAA, MS, IÞ, ÍÓ, EE, ÁJ, TJL, KG, and CUN contributed to acquisition of data and interpretation of results. ST, CVM and SYK drafted the manuscript. ST, CVM, JÞÓ, SR, CB, MNA, SH, OL, KG, CUN, and SYK provided critical review of the manuscript for important intellectual content.
Funding
CVM was funded by the Danish Cancer Society (Grant no. OV25-02363 and R352-A20533) and the Alfred Benzon Foundation. ST was funded by Rigshospitalet Research Foundation and the European Hematology Association. The iStopMM study is funded by the Black Swan Research Initiative of the International Myeloma Foundation, the European Research Council under the European Union´s Horizon program (Grants 716677 and 101045549), the Icelandic Centre for Research (Grants 228524-051 and 217987-051), Blood Cancer United (2340-23), the Rising Tide Foundation (CCR-24-160), the Icelandic Cancer Society, the Landspítali Research Fund, the Nordic Cancer Union, the World Cancer Research Fund (IIG_FULL_2024_040), the International Myeloma Society – Paula and Rodger Riney Foundation Translational Research Award, and the University of Iceland. Screening tests were provided by The Binding Site Ltd., part of Thermo Fisher Scientific. Open access funding provided by National Hospital.
Data availability
De-identified data from iStopMM are available from the corresponding author upon reasonable request, subject to approval by the iStopMM investigators and the Icelandic National Bioethics Committee. Data from the DALY-CARE data resource can be accessed on a collaborative basis within the restrictions from the Danish National Ethics Committee. R codes are available upon request from corresponding author.
Competing interests
ST reports honoraria for scientific presentations from AbbVie, GlaxoSmithKline, Takeda and Thermo Fisher Scientific; advisory board participation for Sanofi; a travel grant from Amgen; and conference participation supported by GlaxoSmithKline outside the submitted work. CVM has participated in a conference supported by Daiichi Sankyo. SR reports honoraria for scientific talks from Johnson & Johnson and Siemens Healthineers. CB has received travel grants from AbbVie and AstraZeneca. CUN has received research funding from AbbVie, Johnson & Johnson, AstraZeneca, the Novo Nordisk Foundation, Genmab, and Octapharma, and has served as a consultant for AbbVie, BeiGene, Janssen, Roche, AstraZeneca, CSL Behring, Genmab, Takeda, Octapharma, MSD, Synamics, and Lilly. KG has received research funding from Janssen. SH is employed at Thermo Fisher Scientific. OL reports grants from Amgen, Johnson & Johnson, and Pfizer; service on independent data monitoring committees for Johnson & Johnson, Takeda, and Merck; and personal fees from Sanofi, Johnson & Johnson, and Pfizer outside the submitted work. SYK reports research funding from Amgen and Celgene and service on an independent data monitoring committee for Johnson & Johnson outside the submitted work. The remaining authors had no conflict of interest.
Ethics approval and consent to participate
The iStopMM study was approved by the Icelandic National Bioethics Committee (Number 16–022, date: 2016-04-26) and the Icelandic Data Protection Agency and all participants provided informed consent. The study in DALY-CARE was approved by the Danish Health Data Authority (P-2020-561) and National Ethics Committee (1804410). Under Danish legislation, register studies are exempt from informed consent.
Footnotes
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
These authors contributed equally: Cecilie Velsoe Maeng, Sigrún Thorsteinsdóttir.
Supplementary information
The online version contains supplementary material available at 10.1038/s41375-026-03028-8.
References
Associated Data
Supplementary Materials
Supplementary
Data Availability Statement
De-identified data from iStopMM are available from the corresponding author upon reasonable request, subject to approval by the iStopMM investigators and the Icelandic National Bioethics Committee. Data from the DALY-CARE data resource can be accessed on a collaborative basis within the restrictions from the Danish National Ethics Committee. R codes are available upon request from corresponding author.